Atherosclerosis and other cardiovascular diseases (CVDs) are the leading cause of death in the United States and Western Europe. As more is known about the potential mechanisms involved in atherosclerotic disease, it has become clear that viruses are critically involved in disease progression. Human cytomegalovirus (HCMV) is a primary viral candidate in the pathology of these diseases because: 1) strong epidemiological evidence links HCMV infection with atherosclerosis; 2) HCMV infection correlates with increased CVD incidence and severity; and, 3) the cells, including endothelial cells, of patients with disease pathology contain HCMV. It is this infection of endothelial cells that appears to be a key event for CVD progression. Endothelial cells provide a non-thrombogenic layer, separating blood from the arterial wall; secrete cytokines and growth factors; and are the first cells to be damaged during disease progression. One of the primary changes seen in the diseased endothelium is an increased vascular permeability (a loss of the integrity of the endothelium) due to the proliferation of endothelial cells. To investigate a possible mechanism for HCMV's role in CVDs, we initiated a study to examine if HCMV infection induces endothelial cell proliferation. The results of these studies showed for the first time that HCMV infection induces bona fide endothelial cell proliferation. Based on these preliminary studies, we hypothesize that infection of these cells and their resulting proliferation is central to HCMV vascular pathobiology. To address this hypothesis, the following specific aims are proposed. First, to determine by flow cytometric analysis, the specific viral mechanisms utilized by HCMV for the induction of endothelial cell proliferation. Second, to delineate using Western blot and electrophoretic mobility shift assays, and gene array technology, the cellular pathways subverted during HCMV infection that induce endothelial cell replication. This proposal will test our hypothesis and provide direct evidence for the molecular mechanisms, utilized by HCMV that affect the biological function of endothelial cells. By utilizing molecular technologies and developing a collaborative environment, the ground work is set for the continued and future investigations of viral infections in vascular disease - supporting our long standing goal of understanding viral-mediated disease pathology.